There is no simple one-marker but different findings:

Michael Berk

[email protected]

has published about this subject.

Berk et al. BMC Medicine 2013, 11:200

http://www.biomedcentral.com/1741-7015/11/200

In studies where healthy participants are given endotoxin

infusions to trigger cytokines release, classical depressive

symptoms emerge . Exogenous cytokine infusions also

cause the classical phenotypic behavioral and cognitive

features of depression. As an exemplar, a quarter of the

people given interferon for the treatment of hepatitis C

develop emergent major depression [8,9]. Intriguingly,

antidepressants, particularly selective serotonin reuptake

inhibitors (SSRIs), in vitro or ex vivo exert significant

negative immunoregulatory effects, decreasing the production

of pro-inflammatory cytokines, for example,

tumor necrosis factor (TNF)α and interleukin (IL)-1,

T cell cytokines, for example, interferon (IFN)γ, and

increasing that of anti-inflammatory cytokines, for

example, IL-10 [10,11]. They additionally alter leucocyte

mRNA gene expression of some immune markers.

Galecki first documented altered expression of mRNA

coding for cyclooxygenase-2, myeloperoxidase, inducible

nitric oxide synthase and secretory phospholipase A2

type IIA in people with recurrent depressive disorder

[12]. Additionally, inflammatory gene expression secondary

to antidepressant therapy has been examined, with

lowered levels of IL-1β and macrophage inhibiting

factors seen after treatment, changes which were not

associated with treatment response. However, lowering

of IL-6 levels was associated with antidepressant

response

In humans, there is evidence that different types of

psychosocial stressors may stimulate the pro-inflammatory

cytokine network, including increases in IL-6 and

TNFα [25-28]. Maes et al. [28,29] were the first to report

that stress-induced increases in IFNγ and stress-induced

Th1 dominance were significantly correlated with stressinduced

anxiety and distress. Thus, subjects with psychological

stress-induced distress and anxiety showed

significantly greater increases in IFNγ and lower IL-10

than those without distress and anxiety. Psychosocial

stress is also accompanied by lowered levels of endogenous,

anti-inflammatory compounds, for example,

CC16 (uteroglobuline), which decreases the production

of IFNγ [30]. Individuals showing stress-induced

decreases in CC16 in the serum display higher stressinduced

anxiety and distress, and an increased production

of IFNγ during the stress condition [29,30]. Thus,

stress-induced increases in pro-inflammatory and Th1-

like cytokines may be mediated by lowered levels of endogenous

anti-inflammatory compounds, such as CC16.

Stress-induced production of pro-inflammatory cytokines,

for example, TNFα and IL-6, and Th1-like cytokines,

for example, IFNγ, are related to an increased

number of leukocytes and neutrophils, and expression of

immune cell activation markers, including CD2+CD26+

and CD2+HLADR, and different signs of an acute phase

response [29]. This indicates that psychosocial stressinduced

elevations in pro-inflammatory cytokines orchestrate

stress-induced changes in peripheral blood

immune cells, inflammatory reactions and neurobehavioral

changes.

The findings that psychosocial stressors modulate the

production of pro-inflammatory versus anti-inflammatory

or negative immunoregulatory cytokines has important

implications for stress-related disorders, including

depression and post-traumatic stress disorder (PTSD).

Psychosocial stressors, such as negative life events,

and chronic psychosocial stress often precede the onset

of clinical depression. Translational models show that

pro-inflammatory cytokines, such as IL-1β, IL-6 and

TNFα, are depressogenic and anxiogenic. These mechanisms

may explain why psychosocial stressors and acute

psychotrauma may trigger mood disorders in vulnerable

subjects, for example, those with immune gene polymorphisms,

lowered levels of pepdidases, including dipeptidylpeptidase

and prolylendopeptidase, and those with

increased inflammatory burden

Clinical

depression has recently been shown to be accompanied

by increased plasma levels of immunoglobulin (Ig) A

and/or IgM directed against a number of gram negative

bacteria, including Hafnia alvei, Pseudomonas

aeruginosa, Morganella morganii, Proteus mirabilis,

Pseudomonas putida, Citrobacter koseri and Klebsielle

pneumoniae [138-140]. All these gram negative bacteria

belong to the normal gut flora [141,142]. These results

suggest that there is an IgA- and IgM-mediated immune

response directed against LPS, which is part of the bacterial

wall of gram negative bacteria. LPS are toxic substances,

which may activate immune cells by binding to

the CD14-Toll-like receptor-4 (TLR4) complex. This in

turn may activate intracellular signaling molecules, such

as nuclear factor (NF)-κβ, which in turn activates the

production of pro-inflammatory cytokines, including

TNFα and IL-1 and cyclo-oxygenase-2 (COX-2)

Summary

First, depression is a very pleomorphic and

heterogeneous phenotype, and there are likely to be substantial

differences in results depending whether studies

examine clinical or non-clinical samples, use cut scores

on rating scales or formal structured interviews and so on.

Similarly, many studies do not control for potential confounders,

and most of the literature is cross-sectional.

Last, the areas of interest diverge greatly in terms of the

quantity and quality of the extant literature, with a clear

picture emerging on some areas, such as trauma and

stress, and others remaining areas for future investigation.

The identification of a number of potential factors that

are known sources of inflammation, and their correlation

to quality evidence linking those factors to increased

risk of depression, provides mechanistic support

for inflammation as one of the mediating pathways to

both risk and neuroprogression in depression. The pivotal

element is that most of these are plastic, and amenable

to intervention, both therapeutic and preventative.

While inflammation has suggested a number of verypromising anti-inflammatory therapies, including statins,

aspirin, pioglitazone and celecoxib, the latter preventative

need is perhaps the more pressing [14,250,251].

Psychiatry largely lacks an integrated model for conceptualizing

modifiable risk factors for depression. It has,

therefore, lacked conceptually and pragmatically coherent

primary prevention strategies, prioritizing the treatment

of established disorders. Yet the rationale, targets

and imperative to focus on prevention of depression at a

population level is clear.

Dear Colleague

Thank you so much for your time and this exhaustive explanation

1.What would be the markers you would suggest to measure / assess in a daily "routine" consultation focused on the occuupational related stress disorders (Burn out , PTSD,MDD, etc) in order to consolidate the clinical diagnostic ?

2. Is the salivary cortisol of any value for this purpose?

3. Many years ago, we were hoping that the dexamethasone suppression test was supposed to be a good marker to confirm the clinical diagnostic of major depressive disporders and to correlate the biological response to the symptoms intensity and the recovery prediction. We abanndonned this test because of the absence of specificity / Sensitivity. What is its added value today?

4.Some colleagues of mine (essentielly GP's) prescribe blood samples to evaluate the concentration of neurotransmitors & metabolites (5HT, DA, NA, MHPG,etc) Based on the results they recommand, special diets, food complements , antidepressive drugs etc . What is you position with that respect. I was thinking that the peripheral metabolites do not reflect nor the clinical central brain condition neither the clinical complaints / picture.

Thank you very much in advance

Best regards

Dr P.Mesters

Please find enclosed some hints regarding the context of exhaustio:

1. Because a person is a whole: body, mind and spirit I would first administer Oldenburg Burnout Inventory (OLBI), and inventories for depression, anxiety, PTSD and self-rated health and long-term sickness absence (LTSA)

See: Burnout Levels and Self-Rated Health Prospectively Predict Future Long-Term Sickness Absence: A Study Among Female Health Professionals

Peterson, Ulla PhD; Bergström, Gunnar PhD; Demerouti, Evangelia PhD; Gustavsson, Petter PhD; Åsberg, Marie MD, PhD; Nygren, Åke MD, PhD

Journal of Occupational and Environmental Medicine

Issue: Volume 53(7), July 2011, p 788–793

2. Salivary cortisol is still of value for this purpose:

Emotional exhaustion and overcommitment to work are differentially associated with hypothalamus–pituitary–adrenal (HPA) axis responses to a low-dose ACTH 1–24 (Synacthen) and dexamethasone–CRH test in healthy school teachers.

Source: Stress [1025-3890] Wolfram, Maren yr:2013 vol:16 iss:1 pg:54

E-mail: [email protected]; Department of Medical Psychology

Experimental protocol

Participants reported twice to our laboratory on afternoons (appointments between 14:00 h and 16:00 h). On the first test day, the ACTH1–24 (Synacthen) sensitivity test was administered, followed by the DEX–CRH test on the second test day. On average, time elapsed between the two tests was 12.2 days ( ± 15.4 standard deviation, SD) with a range of 1–70 days due to individual schedules of subjects. Because of extremely fast elimination of Synacthen from blood (terminal phase reached after 3 h), no spill-over effects are expected for consecutive test days (note: in the present data, time elapsed between test days did not affect any results). On both test days, participants arrived at the laboratory having abstained from alcohol, caffeinated beverages, physical exercise, and a heavy lunch throughout the study day. The first test day involved a short health check by a medical doctor (cardiovascular and anthropometric measures; a chromatographic pregnancy test in premenopausal women). Then, an intravenous catheter was inserted either into the antecubital or the medial cubital vein and a first blood sample (2.7 ml) was taken for the analysis of corticosteroid binding globulin (CBG). Sixty minutes later, at time point − 1 min, a pre-test blood (9 ml) and saliva samples were collected, directly followed by an intravenous injection of a low dose (1 μg) of ACTH1–24 (Synacthen®, Novartis Pharma, Nürnberg, Germany). At time intervals of +15,+30,+45,+60,+90, and +120 min after Synacthen administration, consecutive blood (9 ml) and saliva samples were collected.

The night before the second test day, participants self-administered an oral dose of 1.5 mg dexamethasone (Fortecortin®, Merck, Darmstadt, Germany) at 23:00 h. On the test day, after insertion of the intravenous catheter, participants rested for 45 min. At time point − 1 min, pre-test blood and saliva samples were collected. Immediately afterwards, the HPA axis was challenged with an injection of 100 μg human CRH (Ferring, Kiel, Germany). Further blood (9 ml) and saliva samples were collected +15,+30,+45,+60,+90, and +120 min after hCRH administration.

Biochemical analyses

Venous blood was collected using Monovettes (Sarstedt, Nümbrecht, Germany) for determination of ACTH (Ethylendiaminotetraacetat (EDTA) Monovettes) and total plasma cortisol (EDTA Monovettes) as well as CBG (Serum Monovettes). Saliva samples were collected using Cortisol Salivettes (Sarstedt). Blood samples were immediately stored on ice and centrifuged at 2000 g and 4°C for 15 min in an adjacent room, and plasma or serum was pipetted into aliquots. Aliquots were then frozen at − 20°C until the end of the test day and in the evening at − 80°C until further analysis. Saliva samples were stored at − 20°C. Upon completion of the study, all samples were sent either to the Psychobiological Research Laboratory of the University of Trier, Germany (ACTH, total plasma, and free salivary cortisol) or to IBL International Hamburg, Germany (CBG) on dry ice to be assayed.

Free salivary cortisol was measured in duplicate using a time-resolved immunoassay with fluorometric detection (Delayed Fluorescence Immunoassay (DELFIA), intra-assay variation: 4.0–6.7%, inter-assay variation: 7.1–9.0%). The detection limit was 0.1 nmol/l. For the determination of total plasma cortisol and ACTH concentrations, samples were assayed in duplicate using a commercially available enzyme-linked immunosorbent assay kit (total plasma cortisol: intra-assay variation, 3.2–8.1%; inter-assay variation, 6.5–7.7%; detection limit, 0.1 ng/ml; ACTH: intra-assay variation, 3.1–4.2%; inter-assay variation, 5.8–6.2%). For the determination of CBG concentrations, blood samples from Serum Monovettes were assayed using a commercially available radioimmunoassay kit (intra-assay variation, 2.9–3.9%; inter-assay variation, 2.4–5.5%; detection limit, 0.26 μg/ml).

Statistical analyses

Statistical analyses were carried out using the SPSS statistical software package (IBM SPSS Statistics, Version 19; Chicago, IL, USA). Results are expressed as mean ± SD. For all general linear models (GLMs), F values, degrees of freedom, and p values were corrected according to Greenhouse–Geisser procedure whenever sphericity was violated. The significance level was set at p ≤ 0.05. Effect sizes were calculated by partial eta squared ( ), expressing the amount of variance explained in the dependent variable by the respective effect. Averages of duplicate values (see biochemical analysis) were used in statistical analyses. Rates below detection limit were set at the lowest detectable value. Cortisol and ACTH concentrations were log-transformed before statistical analysis (the figures present untransformed values for illustration reasons).

Test of potential covariates

At first, potentially occurring main or interaction effects of age, sex, BMI, and CBG concentrations on ACTH, total plasma cortisol, or free salivary cortisol concentrations were assessed in a set of ANOVAs for repeated measures for each stimulation procedure. In this way, we checked for any effects of potential covariates on hormonal responses in our sample including men, women taking hormonal contraception, postmenopausal women, and women in the luteal phase. As age did not yield any significant main or interaction effects for either ACTH or cortisol (all p = n.s.) and to avoid overfitting of our GLMs (Babyak 2004), this variable was not included as a covariate in the statistical models (see below). For sex, BMI, and CBG concentrations, significant effects on HPA axis parameters were found and they were thus included as covariates in all subsequent analyses. However, none of these covariates showed significant associations with questionnaire scores (all p = n.s.).

3. Update on dexamethasone suppression:

Sandström, A., Peterson, J., Sandström, E., Lundberg, M., Rhodin Nystrom, I.-L., Nyberg, L. & Olsson, T. (2011). Cognitive deficits in relation to personality type and hypothalamic-pituitary-adrenal (HPA) axis dysfunction in women with stress-related exhaustion. Scandinavian Journal of Psychology 52, 71-82. Exhaustion caused by long-term work-related stress may cause cognitive dysfunction. We explored factors that may link chronic stress and cognitive impairment. Personality, psychiatric screening, and behavior were assessed by self-reporting measures in 20 female patients (mean age 39.3 years; range 26-53) with a preliminary diagnosis of stress-related exhaustion and in 16 healthy matched controls. Cognitive performance was investigated with a detailed neuropsychological test battery. Cortisol axis function was assessed by urinary and saliva collections of cortisol, dexamethasone suppression, Synacthen response, and corticotropin-releasing hormone (CRH) tests. Proinflammatory cytokines were measured. Hippocampal volumes were estimated by magnetic resonance imaging. Multivariate and univariate statistical methods were used to explore putative differences between groups and factors linked to cognitive impairment. Cognitive function clearly differed between groups, with decreased attention and visuospatial memory in the patient group, suggesting frontal cortex/medial temporal cortex-network dysfunction. Increased harm avoidance and persistence was present among patients, with lowered self-directedness linked to lower quality of life, increased anxious and depressive tendencies, and experiences of psychosocial stress. Attention was decreased with concomitantly impaired visuospatial memory. The pituitary (adrenocorticotropic hormone, ACTH) response to CRH was decreased in patients, with an increased cortisol/ACTH response to CRH. However, cortisol production rates, diurnal or dexamethasone-suppressed saliva cortisol levels, and the cortisol response to Synacthen were unaltered. Hippocampal volumes did not differ between groups. These findings suggest that cognitive dysfunction in stress-related exhaustion is linked to distinct personality traits, low quality of life, and a decreased ACTH response to CRH.

4.

Essential role of excessive tryptophan and its neurometabolites in fatigue.

Yamamoto, Takanobu; Azechi, Hirotsugu; Board, Mary. The Canadian Journal of Neurological Sciences / Le Journal Canadien Des Sciences Neurologiques39.1 (Jan 2012): 40-47.

Purpose: Serotonin, a neurotransmitter synthesized from tryptophan, has been proposed to play a key role in central fatigue. In this study, we examined whether tryptophan itself and/or its two metabolites, kynurenic acid (KYNA) and quinolinic acid (QUIN), are involved in central fatigue. Materials and Methods: Experiments were conducted using Sprague-Dawley rats (SDR) and Nagase analbuminemic rats (NAR). Central fatigue was assessed by treadmill running and a Morris water maze test. Microdialysis was used to collect samples for measurement of extracellular concentration of tryptophan, serotonin and 5-hydroxyindoleacetic acid (5-HIAA) and to infuse test agents. To examine the kinetics of release, synaptosomes in the striatum were prepared in vitro to measure intra- and extrasynaptosomal concentration of tryptophan, serotonin and 5-HIAA. Results: The concentration of tryptophan secreted into the extracellular space of the striatum was higher during fatigue only, and quickly returned to basal levels with recovery from fatigue. Running time to exhaustion was reduced by activation of tryptophan receptors. Time to exhaustion was shorter in NAR, which maintain a higher extracellular level of striatum tryptophan than SDR. Impaired memory performance in a water maze task after tryptophan treatment was attributable to high levels of KYNA and QUIN in the hippocampus acting synergistically on N-methyl-D-aspartic acid receptors. When branched-chain amino acids were administered, tryptophan transport to the extracellular space of the striatum was drastically inhibited. Conclusion: Our findings demonstrate that the increase in fatigue which occurs because of excessively elevated brain tryptophan can be further amplified by the use of synthetic KYNA and QUIN.

Sandström, A. Impaired cognitive performance in patients with chronic burnout syndrome. Biological psychology 69.3 (2005): 271-9.

. Kudielka, Brigitte M. Circadian cortisol profiles and psychological self-reports in shift workers with and without recent change in the shift rotation system. Biological Psychology 74.1 (2007): 92-103.

With all good wishes

Béatrice

Here is an email address to a person who probably can answer your questions to your satisfaction: [email protected]

Thank you so much!